Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2001-02-21
2002-11-19
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S464000
Reexamination Certificate
active
06482417
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the formulation of pharmaceutical compositions, and more particularly to novel pharmaceutical formulations for the oral administration of torsemide.
BACKGROUND OF THE INVENTION
1-Isopropyl-3-[(4-m-toluidino-3-pyridyl)-sulfonyl]urea, which is represented by the structural formula
is approved, under the trademark DEMADEX®, by the U.S. Food and Drug Administration, for the treatment of hypertension and edema associated with congestive heart failure, renal disease, or hepatic disease. The USAN approved generic name for this compound is torsemide, although this compound is also referred to as “torasemide” in the art. Torsemide is a loop diuretic that has been found to be particularly effective for the treatment of edema associated with chronic renal failure.
U.S. Pat. No. Re. 30,633 describes a synthesis of torsemide. It is known that torsemide can occur in at least two different crystalline forms, Acta Cryst. 1978, pp. 2659-2662 and Acta Cryst., 1978, pp. 1304-1310, in which the crystal identified by space group P2
1
/c is designated Dupont Form 1 herein and the crystal identified by space group P2
is designated Dupont Form 2 herein. U.S. Pat. No. 4,822,807, which reissued as U.S. Pat. No. Re. 34,672, describes two crystalline forms of torsemide, designated modification I and modification II. Torsemide modification I is defined herein as the torsemide characterized by the x-ray powder diffraction pattern of
FIG. 1
, in the 37 C.F.R. § 1.132 declaration by Dr. Fritz Topfmeier filed on Dec. 30, 1987, which is located in the file wrapper of U.S. Pat. No. 4,822,807 (the “Topfmeier Declaration”). Torsemide modification II is defined herein as the torsemide characterized by the x-ray powder diffraction pattern of
FIG. 2
, in the Topfmeier Declaration.
Topfmeier and Lettenbauer have described in U.S. Pat. No. 4,822,807 that when torsemide of modification II is present in very finely divided form in pharmaceutical tablets, it rearranges into torsemide modification I, with the result that the rate of dissolution of the active material upon introducing the tablets into water can be significantly changed. The dissolution rate is an important characteristic of a pharmaceutical dosage form and, in order to dose reproducibly, must not differ from one tablet to the next.
Thus, there remains a need in the art for pharmaceutical formulations containing torsemide modification II, wherein the torsemide does not rearrange into torsemide modification I and that are stable with regard to dissolution rate.
SUMMARY OF THE INVENTION
Stable pharmaceutical formulations containing torsemide modification II, wherein, upon storage under stress conditions, the torsemide modification II does not rearrange into torsemide modification I and wherein the stable pharmaceutical formulations are also stable with regard to dissolution rate in solution, have been discovered.
Additionally, a high purity torsemide modification II which is substantially free of other forms of torsemide and processes for making the high purity torsemide modification II have also been discovered.
The present invention relates to high purity torsemide modification II that does not substantially rearrange into a different form of torsemide over time upon storage in bulk under stress conditions, e.g., 40° C., 75% relative humidity. Preferably, the high purity torsemide modification II does not substantially rearrange into torsemide modification I over time upon storage in bulk under stress conditions, e.g., 40° C., 75% relative humidity.
The present invention also relates to a stable pharmaceutical formulation comprising an effective amount of torsemide modification II and a pharmaceutically acceptable excipients wherein the excipients have a low moisture content. Preferably, the stable pharmaceutical formulation further comprises the excipients lactose anhydrous, crospovidone, povidone, microcrystalline cellulose, and magnesium stearate all of which having a low moisture content. Preferably, the stable pharmaceutical formulation comprises torsemide modification II in an amount of about 2.5 mg to about 200 mg per tablet. More preferably, the stable pharmaceutical formulation comprises torsemide modification II in an amount of 2.5 mg, 5 mg, 10 mg, 20 mg or 100 mg.
The present invention also relates to stable pharmaceutical formulations comprising an effective amount of torsemide modification II wherein the torsemide modification II does not substantially rearrange into another form of torsemide over time upon storage under stress conditions, e.g., 40° C., 75% relative humidity. Preferably, the torsemide modification II of the stable pharmaceutical formulations does not substantially rearrange into torsemide modification I over time upon storage under stress conditions. Torsemide modification II suitable for use in the present stable pharmaceutical formulations includes high purity torsemide modification II and torsemide modification II containing trace amounts of torsemide modification I. Trace amounts, as defined herein, are amounts of torsemide modification I that are about 0.5-2% by weight of the torsemide modification II (w/w % of torsemide modification I/torsemide modification II).
The present invention relates to stable pharmaceutical formulations comprising an effective amount of torsemide modification II wherein the torsemide modification II has a particle size distribution such that 100% is below 200 &mgr;. Preferably, the particle size distribution is such that 100% is below 100 &mgr;. More preferably, the particle size distribution is such that 100% is below 50 &mgr;.
The present invention also relates to stable pharmaceutical formulations comprising an effective amount of torsemide modification II wherein the dissolution rate in vitro of the stable pharmaceutical formulation, when measured by the U.S.P. Paddle Method at 50-90 RPM in 900 mL water, is not less than 80% (by weight) of the torsemide modification II released after 30 minutes. Preferably, the dissolution rate in vitro does not substantially change over time upon storage in bulk under stress conditions, e.g., 40° C., 75% relative humidity. More preferably, the dissolution rate in vitro does not substantially change during storage under stress conditions for at least 3 months.
The present invention also relates to a process for making high purity torsemide modification II wherein the high purity torsemide modification II is purified from crude modification II by the novel combination of two purification steps known in the art wherein the novel process comprises the steps of (1) reslurrying crude torsemide modification II followed by (2) crystallization to yield high purity torsemide modification II by the methods of U.S. Ser. No. 09/638,106; filed Aug. 11, 2000, the contents of which are incorporated herein by reference
REFERENCES:
patent: RE30633 (1981-06-01), Delarge et al.
patent: 4822807 (1989-04-01), Topfmeier et al.
patent: RE34672 (1994-07-01), Topfmeier et al.
patent: 5738872 (1998-04-01), Ortyl et al.
patent: 5914336 (1999-06-01), Dreckmann-Behrendt
Acta Crystallographica, vol. B34 Part 4, Apr. 15, 1978 (pp. 1051-1400).
Acta Crystallographica, vol. B34 Part 8, Aug. 15, 1978 (pp. 2387-2672).
Aronhime Judith
Kopel Mira
Kordova Marco
Leibovici Minutza
Tenengauzer Ruth
Dees Jose′ G.
Gollamudi Sharmila S.
Kenyon & Kenyon
Teva Pharmaceutical Industries Ltd.
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